Predicting proton titration in cationic micelle and bilayer environments

Area of Science:

• Biophysical Chemistry
• Computational Chemistry
• Materials Science

Background:

• Protonation behavior of pH-sensitive molecules in complex environments like micelles and bilayers is vital for consumer products and biomedicine.
• Traditional structure-based calculations struggle to accurately determine pKa values in these systems.
• Understanding these behaviors is key to developing improved fabric care products and analyzing drug side effects.

Purpose of the Study:

• To calculate the pKa of a fatty acid molecule in different lipid environments (micelles, liquid bilayers, gel bilayers).
• To investigate the influence of molecular dynamics simulations with explicit ions and titratable water on pKa calculations.
• To demonstrate the capability of all-atom constant pH molecular dynamics in capturing complex energetic interactions.

Main Methods:

• Utilized all-atom constant pH molecular dynamics simulations.
• Incorporated explicit ions and titratable water in the simulations.
• Calculated the pKa of a fatty acid in dodecyl trimethylammonium chloride micelles and diethyl ester dimethylammonium chloride liquid/gel bilayers.

Main Results:

• The pKa of the fatty acid in the gel bilayer was found to be 5.4.
• This pKa is 0.4 units lower than in the analogous liquid bilayer or micelle.
• This reduction occurred despite increased desolvation of the protonated carboxylic group in the gel bilayer, highlighting complex free energy contributions.

Conclusions:

• All-atom constant pH molecular dynamics accurately captures the interplay between desolvation and Coulombic interactions influencing pKa.
• Explicitly treating ions is essential for accurately sampling protonation states in molecular simulations.
• This simulation approach advances the modeling of pH-responsive molecules in bilayers, benefiting product development and drug interaction studies.